Journal of Investigative Medicine:
EB Symposium Manuscripts
Natriuretic Peptides as Biomarkers in Heart Failure
Januzzi, James L. Jr MD
From the Cardiology Division, Massachusetts General Hospital, Boston, MA.
Received March 22, 2013.
Accepted for publication March 27, 2013.
Reprints: James L. Januzzi, Jr, MD, Cardiology Division, Massachusetts General Hospital, Yawkey 5984, 55 Fruit St, Boston, MA 02114. E-mail: email@example.com.
Presented at Experimental Biology 2013.
This symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236). Dr. Januzzi is supported in part by the Roman W. Desanctis Endowed Distinguished Clinical Scholar Fund. He also has received grant support from Roche Diagnostics, Siemens AG, BG Medicine, Thermo Fisher, and Critical Diagnostics.
Abstract: Following the initial discovery of a natriuretic and diuretic peptide factor present in atrial myocardial tissue homogenates, subsequent elucidation of the natriuretic peptide (NP) family has led to substantial advances in the understanding of the autocrine, paracrine, and endocrine regulation of the cardiovascular system. Furthermore, with the development of assays for the measurement of the NPs, these important biomarkers have gone from being regarded as biological mediators of the cardiovascular system to now represent important clinical tools for the diagnostic and prognostic evaluation of patients with heart failure and may have potential as a therapeutic target in this setting as well. An historical perspective on the NPs from bench to bedside translation will be discussed.
Over the past 3 decades, considerable efforts in the study of the natriuretic peptide (NP) family of protein hormones have led a better understanding of the role played by these important substances in the development and complication of various medical conditions, including heart failure (HF). Beyond shedding important light on the complex biological pathways involved in NP-based cardiovascular homeostasis, elucidation of NP biology has also led to the development of sensitive immunoassays for their measurement in peripheral blood. Concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in particular have been deeply studied for their role in a host of diagnoses, including HF, with results demonstrating utility for these biomarkers as tools to establish diagnosis, understand prognosis, and ultimately potentially serve as a target for therapy. This discussion examines the historical background of the NP family, specifically focusing on ANP and BNP, with a discussion of their biology, and how these peptides may be clinically utilized.
HISTORY OF THE NPs
Following very early electron microscopy studies in the 1950s revealing dense granules comparable to those found in glandular tissue located in the atrial myocardium, a consensus developed around the concept of the heart as an endocrine organ. The seminal work of Adolfo de Bold in 1981 led to the discovery of ANP, following observations that the presence and density of atrial granules changed with intravascular volume, experiments were performed where intravenous injection of atrial myocardial extracts led to a rapid diuretic and natriuretic response in rats. Subsequent isolation and identification of the peptides responsible for this effect led to the first descriptions of the NP family.
EVOLUTION OF THE NP FAMILY
The NP family is believed to have evolved for the common homeostatic purpose of volume, osmosis, and pressure regulation of the circulatory system. More recently, evidence supports the concept that this family of cardiovascular peptides has also played an autocrine and paracrine role in the control of myocardial structure and function as well.1,2 The known NP system in human and nonhuman vertebrates consists of at least 6 “cardiovascular” peptides ANP, BNP, C-type natriuretic peptide, dendro aspis natriuretic peptide, and V-type natriuretic peptide. as well as a “renal” NP, urodilatin. Although each member of the NP family appears to exert vasodilator or venodilator effects and may induce diuresis and natriuresis, the relative balance of these effects varies somewhat from peptide to peptide.
The NP system is phylogenetically preserved with both components (endocrine and paracrine) identified in the heart and brain of a wide range of species, including teleost fish, amphibians, reptiles, birds, and selected species of mammals (human, cat, cattle, dog, mouse, rat, sheep, and swine).3 Across all species, CNP is the most structurally conserved member of the NP family,3 whereas BNP and its amino-terminal prosegment NT-proBNP differ even between mammalian species3; as such, the human BNP 5, flanking sequence is 65% and 77% homologous with the rat and mouse BNP genes, respectively, whereas the rodent proximal promoters are greater than 90% homologous.4 It has been suggested that the NP system evolved from being sodium-extruding hormones in fish to volume-depleting hormones in tetrapods.5
Downstream biologic effects of the NPs are well known; in the case of ANP and BNP, these include vasodilation, natriuresis, and diuresis; in addition, BNP may downregulate the renin-angiotensin aldosterone system. Brain natriuretic peptide may have an antifibrotic effect on the heart muscle6 as the phenotype of BNP “knockout” mice is one of myocardial fibrosis with abnormal remodeling in the setting of ventricular pressure overload.6 Lastly, BNP also appears to possess pro-lusitropic properties.7
ANP AND BNP TISSUE EXPRESSION
Notable stimuli for ANP and BNP gene expression, transcription and translation include mechanical stretch,8,9 ischemic injury/hypoxia,10 endothelin 1,11 angiotensin II,12 interleukin 1β,13 and α- and β-adrenergic agonists,13 among others.
The great majority of ANP is synthesized and stored in atrial tissue. In contrast, whereas BNP appears to be more abundant in the atria than in the ventricles, given the greater ventricular mass, 70% of all cardiac BNP derives from the ventricles under normal conditions and up to 88% under pathophysiologic conditions.14 Additionally, in contrast to ANP, most BNP is synthesized in bursts of activation from physiologic stimuli15 and “emergently” increased when peptide secretion is called upon, rather than being stored.
Extracardiac sources of BNP in humans have been found in brain, lungs, kidneys, aorta, and adrenal glands at much smaller concentrations.16 As such, the majority of BNP gene expression in mammals has been found to be in the heart, with extracardiac BNP expression being more species-specific, and in all cases much lower than cardiac levels.17
NP Processing and Secretion
Each NP gene produces a prohormone from which the active peptide is generated. In the case of ANP, an initial 126-amino-acid precursor is cleaved to yield a 96-amino-acid N-terminal propeptide and a 28-amino-acid C-terminal fragment. The latter peptide is biologically active, with an extremely short half-life after secretion, because of degradation. It remains yet unclear if uncleaved proANP1-126 circulates in any significant amount.
Following translation of the BNP gene, an initial gene product is produced, pre-proBNP1-134. This peptide undergoes rapid removal of a 26-amino-acid signal peptide, which results in the formation of a 108-amino-acid prohormone, proBNP1-108.18 Subsequently, proBNP1-108 is cleaved by proteolytic enzymes furin19 and corin20 to release 2 portions: a 76-amino-acid amino-terminal portion, NT-proBNP1-76, and the biologically active 32-amino-acid molecule BNP1-32, which possesses a characteristic 17-amino-acid disulfide-bound ring essential for biological activity.
A substantial shift in the understanding of NP secretion has occurred in recent years. Early studies using radioimmunoassays to evaluate BNP in HF actually suggested the presence of both high- and low-molecular-weight forms of “BNP,” with high-molecular-weight BNP being the major component (mean ratio, 1.9:1).21 More recent studies have used Western blot analysis techniques to better characterize these immunoreactive BNP species in HF plasma and have confirmed that there are both low-molecular-weight BNP forms (similar to BNP1-32) and higher molecular-weight forms of BNP similar to recombinant proBNP1-108.22 Regarding NT-proBNP, because the N-terminal region of proBNP1-108 contains sequences permitting oligomerization, a trimer of NT-proBNP1-76 has been described.23 Also, fragmentation of NT-proBNP1-76 occurs because proteolysis can exist at both carboxy- and amino-terminal ends of the molecule.24 Therefore, a number of molecules larger and smaller than NT-proBNP1-76 are present in the circulation. Lastly, NT-proBNP is variably glycosylated.25
In the case of ANP and BNP, important mechanisms of removal from circulation include receptor-mediated clearance, enzymatic degradation, and passive removal. Biologically inactive propeptides from both are cleared passively.
There are at least 3 types of NP receptors: NPR-A and NPR-B (the guanylyl cyclase–coupled receptors responsible for biologic effects) as well as NPR-C, the short cytoplasmic domain receptor, responsible for peptide clearance and possibly regulation of cell proliferation. Enzymatic degradation of the NPs is carried out by several peptides, including neutral endopeptidases, dipeptidyl-peptidase IV26 as well as by the peptidase meprin A, which is expressed in the kidney.27 Passive removal from the bloodstream is an important mode of NP metabolism. Several organs with high blood flow have been shown to clear BNP and NT-proBNP, for example, including the musculature, liver, spleen, brain, lungs, and kidneys.28 The relative contribution of the kidneys to removal of BNP and NT-proBNP from the bloodstream remains extremely controversial. The results of carefully performed mechanistic studies suggest that the renal extraction ratio of both BNP and NT-proBNP is equivalent and only about 15% to 20%.29
The understanding of ANP and BNP biology has substantial importance relative to the development and understanding of assays for their measurement. For example, following many years of attempting to reliably measure ANP, it became clear that a novel approach was needed due to the lability of the protein. Accordingly, an immunoassay directed against the midregion of proANP1-96 (MR-proANP) has been developed, which has been shown to be useful for quantifying circulating ANP as a surrogate.
Based on the discussion above, it is understandable that available commercial assays for detection of “NT-proBNP1-76” or “BNP1-32” actually measure more than the individual peptides: in the case of NT-proBNP, assays likely are detecting NT-proBNP1-76 plus variable amounts of proBNP1-108. For BNP, conventional assays likely detect various degradation products of BNP1-32, including BNP3-32 in addition to intact proBNP1-108.22 Despite this fact, assays for the measurement of both NT-proBNP and BNP have been shown to be of considerable utility for clinical evaluation of HF.
CLINICAL APPLICATIONS: NPs TO DIAGNOSE HF
Many patients presenting with acute dyspnea (including those with acutely decompensated HF [ADHF]) have multiple coexisting medical disorders that may complicate their diagnosis and management. Diagnostic uncertainty in the setting of acute dyspnea is associated with longer hospital length of stay, more diffuse diagnostic and therapeutic efforts, increased health care costs, and higher likelihood for repeat HF hospitalization or death.30 It is in this context that the clinical value around the use of NP assays has developed. The addition of testing for MR-proANP, BNP, or NT-proBNP to standard clinical assessment has been shown to be valuable for an accurate and efficient diagnosis and prognostication of HF, and the use of BNP or NT-proBNP may be associated with improved clinical outcomes.31
Concentrations of MR-proANP, BNP, and NT-proBNP are increased in HF and correlate well with ventricular wall stress and severity of HF.32,33 The Breathing Not Properly33 and Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE)32 studies first showed that NP levels were more accurate for diagnosis or exclusion of ADHF than clinical judgment, particularly in the context of diagnostic uncertainty.34 When added to comprehensive clinical assessment, BNP or NT-proBNP are both incrementally useful for diagnosis of ADHF and are both endorsed in current practice guidelines for HF evaluation (particularly when diagnostic indecision is present). Subsequently, the Biomarkers in Acute Congestive Heart Failure and PRIDE studies showed diagnostic value to MR-proANP.35,36 Interestingly in both studies, concentrations of MR-proANP appear to be additive to BNP or NT-proBNP for the diagnosis of ADHF, suggesting contribution of different pathologies to their release.
Elevated NP concentrations are powerfully associated with the presence of HF; however, there is no value for any NP assay that is 100% diagnostic for the diagnosis. Indeed, MR-proANP as well as BNP/NT-proBNP may be elevated by structural heart disease of many sorts (Table 1) and may be abnormal in noncardiac syndromes (Table 2), and patient factors may variably influence the results further (Table 3).
Although experience with MR-proANP is limited outside acute dyspnea evaluation, abundant data are now available showing that both BNP and NT-proBNP may be useful in the differential diagnosis of dyspnea in less acute settings, such as in primary care. In this context, values for both peptide supplement clinical judgment and are particularly useful to exclude the diagnosis of HF in those with very low concentrations of BNP/NT-proBNP.
NPs AND PROGNOSIS IN HF
Across all stages of HF, elevated NP concentrations are at least comparable prognostic predictors of mortality and cardiovascular events relative to traditional predictors of outcome in this setting, with higher values predicting worse prognosis in a linear fashion. For example, in very complex analyses designed with a goal to produce the most parsimonious prognostic model, NT-proBNP was among the strongest long-term prognostic variables in the PRIDE study.37 This prognostic value may be used to stratify patients at the highest risk of adverse outcomes. Interestingly, in analogy to its additive value with BNP or NT-proBNP to identify HF, concentrations of MR-proANP also appear to add to prognostic models even in the presence of either BNP or NT-proBNP.36
A unique value of the NPs for prognosis is the ability to measure them serially to provide dynamic prognostic information. For example, in ADHF, an initial value of BNP or NT-proBNP is prognostically useful. However, a follow-up measurement after therapy provides incremental prognostic value.
Observational studies suggest that when BNP/NT-proBNP concentrations decrease substantially during hospitalization, a better prognosis is expected compared with those that fail to decrease or actually increase their values.38 In a similar fashion, in patients with ambulatory HF, serial concentrations of BNP or NT-proBNP inform incremental prognostic information to a baseline value: those with rising concentrations of either peptide over time have a worse prognosis than those with a low or falling pattern.39 Adverse events predicted by the NPs include death, as well as HF hospitalization, cardiac arrhythmias such as ventricular tachycardia and atrial fibrillation, and worsening ventricular function due to progressive myocardial remodeling.
A curious link between NP concentrations and therapies for HF exists. It is now well recognized that therapies with benefits for HF may result in a reduction in concentrations of NP relative to their benefits. For example, loop diuretics result in potent diuresis and reduction in myocardial stretch (itself an important trigger for NP secretion); in this context, reductions in NP concentrations typically follow the clinical decongestion of the patient. Beyond diuretics—which have little benefit beyond symptomatic relief of HF—several other classes of drugs (each with potent prognostic benefit in HF; Table 4) have been shown to reduce values of BNP and NT-proBNP (few data are available regarding MR-proANP). In light of this link, the use of BNP or NT-proBNP as a target of HF therapy is a testable hypothesis recently explored.
NPs FOR GUIDED MANAGEMENT OF HF
The concept of using BNP or NT-proBNP as a “guide” to HF management is not new, but clarity about the appropriate means by which to implement the approach has been gained in recent years. Important concepts needed to support correct application of NP-guided HF care included the identification of the “target value” for either peptide, an understanding of biological variability for each, and the appropriate timing for resampling when measuring them serially.
As is implied above, concentrations of BNP or NT-proBNP rise in proportion to the risk in HF, and there is no concentration above the very low values seen in healthy individuals that is reassuring. However, consensus has developed that it is possible to identify BNP or NT-proBNP values that may represent an inflection point for risk of HF complications; below these values, risk is considerably lower. In the Valsartan Heart Failure Trial, for example, a BNP value of 125 pg/mL and an NT-proBNP value near 1000 pg/mL provided prognostic value40; above these levels, the risk for complications rose monotonically, whereas below, the risk was low. In other analyses, such as the PRIDE study, an NT-proBNP of 1000 pg/mL again was found to be the appropriate level where risk of HF complications began to rise.41 It is no surprise, therefore, that HF studies targeting values of BNP or NT-proBNP higher than these concentrations were unsuccessful.42
Following a therapy alteration, a change in concentration in BNP or NT-proBNP may follow; such changes may be substantial; however, it is necessary to understand just how much change in the concentration of either needs to occur before a definitive change in the biologic milieu determining their levels can be declared. To do so, a better understanding of biological variability is needed. Biological variability is defined as the expected amount of change over time in concentration of any biological measure independent of significant abnormalities in physiology; it is determined by analytical precision of the assays used to measure the peptides (typically <5%) together with the changes in usual physiology of patients with HF. Recent data suggest week-to-week biological variability of BNP or NT-proBNP to be approximately 30% in HF patients; changes greater than this amount are to be considered as reflecting a significant change in the abnormal physiology triggering BNP or NT-proBNP release. As well, following a change in therapy, it is worth noting that it may take time to achieve a new steady state of BNP or NT-proBNP transcription and translation; whereas studies are lacking regarding the time when a nadir in either peptide may occur after a change in therapy, it is known that by 2 to 4 weeks, a lack of significant change in BNP or NT-proBNP is a high-risk feature.
With a good understanding of the factors that underlie appropriate interpretation and response to BNP or NT-proBNP results, it is therefore easy to understand the results of trials that set out to guide HF with a goal to lower BNP or NT-proBNP (Table 5). It is also worthwhile to note that 2 published meta-analyses of the biomarker-guided approach to HF care have shown a significant reduction in all-cause mortality.52,53
Across each of the published trials, the approach of biomarker-guided HF care was well tolerated, without an excess of adverse events associated with the approach. As well, whether successful or not, the added goal of lowering BNP or NT-proBNP resulted in more substantial addition and uptitration of medical therapies, compared with the usual-care group in the great majority of trials; in itself, this is an important finding, given the current climate of inadequate HF care that exists.
In those trials setting out with a goal BNP or NT-proBNP close to the target values articulated above, improved outcomes were observed; in contrast, as noted, those with higher targets were typically neutral. To achieve lower NP targets, aggressive care was needed, as shown in the several positive trials where addition and uptitration of HF medications were considerably more assiduous in the NP-guided arms.50,51
Insight into the benefit of NT-proBNP–guided HF care was gained from the recent ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) trial.51 In this small but detailed single-center trial, 151 subjects with HF due to left ventricular systolic dysfunction were randomized to receive standard HF care versus standard care plus a goal to reduce NT-proBNP less than 1000 pg/mL. In this study, substantial uptitration of therapies occurred in both arms, but the NT-proBNP–guided patients had significantly more drug therapy changes. In this context, more lowering of NT-proBNP occurred in the biomarker-guided arm, with a parallel reduction in adverse outcome. Patients in the biomarker-guided arm of the trial had significantly better quality of life compared with the standard-care participants54 and also experienced substantially greater favorable remodeling on their echocardiograms.55 Conversely, nonresponders to HF care in the PROTECT study had worse clinical outcomes, worse quality of life, and more deleterious myocardial remodeling.56
While in aggregate, or in the case of several studies such as PROTECT, the results of NP-guided HF studies appear favorable, what is needed at present is a pivotal, prospective multicenter trial to properly inform steps forward with the approach. In 2013, the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE IT; www.clinicaltrials.gov NCT01685840) study initiated enrollment. This multicenter trial of 1100 participants will examine the value of HF therapy with or without a goal of NT-proBNP reduction less than 1000 pg/mL.
From their initial discovery as important hormones involved in regulation of various pathways in normal and abnormal physiology including HF, the NP family of proteins has taken on a significant importance in medicine. Both BNP and NT-proBNP are tested worldwide for the evaluation and management of patients with suspected or proven HF; recent development of an MR-proANP assay has led to encouraging early results with this biomarker. Whether the successes of BNP and NT-proBNP will be repeated or enhanced with MR-proANP remains to be seen. Irrespectively, testing for BNP and NT-proBNP has entirely transformed the diagnostic and prognostic evaluation of patients with a broad range of HF presentations, and their use to better care for patients with HF may further alter the course of modern cardiology.
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natriuretic peptides; biology; diagnosis; prognosis; therapy
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